Pyrazole methylalkyl sulfoxides

ABSTRACT

5- OR 6-MEMBERED HETEROCYCLIC ALKYL SULFOXIDES SUCH AS THIOPHENE, PYRROLE, PYRAZOLE, IMIDAZOLE, THIAZOLE, OXAZOLE, ISOXAZOLE, PYRIDINE, QUINOLINE, PYRAN, ISOTHIAZOLE, FURAN, INDAZOLE, BENZIMIDAZOLE, BENZOXAZOLE, BENZISOXAZOLE, BENZOTHIAZOLE, BENZODIOXANE AND INDOLE DERIVATIVES HAVING ANTIINFLAMMATORY, ANALGESIC AND ANTI-PYRECTIC ACTIVITY.

Unite States atent Shen et al. 1 Sept. 12, 1972 [54] METHYLALKYL [56]References (Ilted XIDES UNITED STATES PATENTS [72] Inventors: Tsung-YingShen, Westfield; Alexand" Matzuk Colonia; Conrad 3,014,916 12/1961 Wrght ..260/3l0 R P. Dorn, Jr., Plainfield, all of NJ. g gr er [73]Assignee: Merck & Co.,lnc., Rahway, NJ. u [22] Filed: June 10, 1970Primary Examiner-Natalie Trousof Attorney-Martm L. Katz, Harry E.Westlake, Jr. and [21] Appl. No.: 45,215 I, Louis Wolk Related US.Application Data 57] ABSTRAQT [62] 1 1? 222x3 P 5- or 6-memberedheterocyclic alkyl sulfoxides such i '2 g ggg as thiophene, pyrrole,pyrazole, imidazole, thiazole, a oxazole, isoxazole, pyridine,quinoline, pyran,

isothiazole, furan, indazole, benzimidazole, benzox- [52] "260/310260/309 260/310 azole, benzisoxazole, benzothiazole, benzodioxane andInt Cl C 232 /13 indole derivatives having anti-inflammatory, analgesic[58] Field of Search ..260/3 10 R and ann'pyrecnc acuvlty 3 Claims, N0Drawings PYRAZOLE METHYLALKYL SULFOXIDES This is a division ofapplication Ser. No. 783,430, filed Dec. 12, 1968, now U.S. Pat. No.3,551,444 which is a division of application Ser. No. 592,977, filedNov. 9, 1969 now U.S. Pat. No. 3,438,992.

This invention relates to a method of treating inflammation utilizingnovel anti-inflammatory compositions containing heterocyclylmethyl alkylsulfoxides. In addition, these novel compositions exhibit potentanalgesic and anti-pyretic activity and, therefore, this invention alsorelates to analgesic and anti-pyretic methods and compositions. Moreparticularly, this invention is concerned with the use ofheterocyclylmethyl alkyl sulfoxides as the active therapeutic ingredientin pharmaceutical compositions.

This invention also relates to certain novel sulfoxides of thestructural formula:

and processes for their preparation, as well as intermediates therefor,wherein l-let" represents or 6- membered heteroaromatic ring compoundshaving less than three rings. The heteroaromatic rings may contain oneor more nitrogen or sulfur atoms; or an oxygen atom together with one ormore oxygen, nitrogen or sulfur atoms. Examples of such heteroaromaticrings include thiophene, pyrrole, pyrazole, imidazole, thiazole,oxazole, isoxazole, pyridine, quinoline, pyran, isothiazole, furan,indazole, benzimidazole, benzoxazole, benzisoxazole, benzothiazole,benzodioxane and indole. The heteroaromatic nucleus may be substitutedwith one or more hydrocarbon groups or with functional substituents(shown as Y,, above, wherein n is 0-2). The hydrocarbon group includesparticularly the lower alkyl, such as methyl, ethyl, propyl, and butyl;and also includes an unsaturated radical such as lower alkenyl or vinyl,and a cyclic aliphatic residue (cyclic lower alkyl) such as cyclopropyl,cyclopentyl and cyclohexyl. The term functional substituent refers to asubstituent other than hydrogen or hydrocarbons. The functionalsubstituents include halo, especially chloro, bromo or fluoro, amino,lower alkylamino, di(lower alkyl)amino, hydroxy, lower alkoxy, mercapto,lower alkylmercapto and nitro. More particularly, this invention relatesto compounds of the formula:

l CH2SOR wherein Y may be hydrogen, hydroxy, halogen, lower alkyl, loweralkoxy, or nitro; and R is lower alkyl.

The carbon atom a to the heterocyclic moiety may contain hydrogen or besubstituted with a lower alkyl or lower alkenyl group (R and R K, may belower alkyl or lower alkenyl. It is preferred that R and R, be hydrogenand R lower alkyl.

The heterocyclylmethyl methyl sulfoxides of this invention represent anew milestone in the continuing search for potent, low toxicity,anti-inflammatory agents. These sulfoxides provide a uniquestructure-activity relationship which not only has resulted in highanti-inflammatory, anti-pyretic, and analgesic potency, but also appearto exhibit a biological profile quite different from the salicylates andphenylbutazone.

The above defined sulfoxide compounds are ad ministrated to a patient ina dosage unit form, a pharmaceutically acceptable composition containinga therapeutically effective amount of a heterocyclylmethyl methylsulfoxide such as 4-methylsulfinylmethylthiazole.

A preferred embodiment of this invention is a method of treating adisease which is symptomatically characterized by pain, fever and/orinflammation which comprises the administration to a patient in dosageunit form of between about 0.01 and 5 gm. of the heterocyclylmethylaliphatic sulfoxide per day. On a kilogram basis, it is preferred toutilize between about 0.5 mg./kg. and mg./kg. per day of theheterocyclylmethyl aliphatic sulfoxide of this invention.

Another embodiment of this invention is the provision of pharmaceuticalcompositions in dosage unit form which comprise from about 5 to 500 mg.,and preferably from 25 to 250 mg., of the heterocyclylmethyl aliphaticsulfoxide of the above formula. 4- Methylsulfinylmethylthiazole, in oraldosage form, comprising about 25 to about 500 mg. is a preferredpharmaceutical composition of this invention.

In a preferred embodiment of this invention, the novelheterocyclylmethyl aliphatic sulfoxides (I) wherein R and R are eachhydrogen, are prepared by reacting a compound having formula (II) withan alkali metal R mercaptide (Ill), to form a heterocyclylmethylthiocompound (IV), which is then oxidized to form compound (I); asillustrated by the following reaction scheme:

I (Y) r-Het- Hg- S O-R4 wherein X represents chloro, bromo or iodo and Mrepresents an alkali metal atom.

The above reaction takes place by adding a heterocyclic halomethylcompound (II) to an alcoholic solution of an alkali metal R -mercaptide(III), prepared by adding an R -mercaptan to an alcoholic solution of analkali metal hydroxide, to form compound (IV) (process step 1) andoxidizing compound (IV) to the desired heterocyclylmethyl R -sulfoxide(1) (process step 2). When an acid salt of compound (II) is used, it ispreferred that an alkaline agent, such as potassium hydroxide be addedfirst to the solution of compound (II) before adding compound (II) tothe basic mercaptide solution (III).

It is preferred that the reaction mixture in step I) be basic. Generallythe reaction mixture is basic because the R -mercaptide reactant impartsbasicity to the mixture. However, the point at which the reactionmixture is made basic is not critical and therefore if it is desired,

compound II and compound III may be mixed in an inert solvent to whichis then added a strong base. It is preferred to reflux the mixtureovernight; however, reaction temperature and time are not critical andtherefore, any suitable time and temperature may be used. The solventused for this reaction is preferably ethanol, however any inert solventwhich is capable of dissolving the reactant may be used. The ratio ofreactants may be varied, however it is preferred to carry out thereaction using an excess of R -mercaptide. The oxidation step 2 may becarried out employing any number of oxidizing agents. Such agents aschromic acid, permanganate, peroxide and alkali metal metaperiodate areamong those which can be used. It is preferred, however to use sodiummetaperiodate as the oxidizing agent. In the selection of an oxidizingagent, the probability of destroying the heterocyclic function to anyextent should be considered. Therefore, it is preferred to sue oxidizingagents such as metaperiodate which are incapable of destroying theheterocyclic moiety. It is preferred to use a ratio of 1:1 of oxidizingagent to compound (IV); Using less oxidizing agent will reduce the yieldand the use of excess oxidizing agent will further oxidize the sulfoxidecompound (I) to the corresponding sulfone.

Generally, the chloro derivative of heterocyclic reactant (II) (X=Cl) ispreferred because of its greater availability. If the chloro-derivativeis insufficiently reactive for practical purposes, the chloro group inreactant (II) may be replaced by iodo, for example, by heating with analkali metal iodide.

In the alternative, the reaction of a (Y),,I-IetCH Cl compound (II) withthe alkali metal R -mercaptide (III) may be carried out in the presenceof a small amount of an alkali metal iodide as a catalyst. Theheteroaromatic ring compounds (II) where X is halogen are known in someinstances. They can also be prepared by known techniques.

In a preferred embodiment of this invention, the CH Cl group isintroduced into the heterocyclic ring by reaction with the formaldehydeand dry I-ICl, in the presence of a condensing agent such as zincchloride. In the alternative this reaction can be carried out in twosteps by reacting the heterocyclic compound with an aqueous solution offormaldehyde and aqueous HCl to give the hydroxymethyl substituent,which may be converted into the chloromethyl derivative by reaction withthionyl chloride.

The hydroxymethyl derivative may be prepared also from a heterocycliccompound already having a forrnyl substituent (CHO) by reduction, forexample, with sodium borohydride; or from a heterocyclic compound havinga carbonylethoxy substituent (COOC H by reduction, for example, withlithium aluminum hydride. The carbonylethoxy substituent (COOC I-I maybe derived from a corresponding carboxy susbstituent (COOH) byesterification. The carboxy substituent in turn may be obtained byoxidation of a methyl substituent, all by methods known in the art.Thus, a halomethyl substituent of the heterocyclic reactant (II) may beintroduced into the heterocyclic ring directly, or derived from a knownheterocyclic compound which has a methyl, carboxy, carbonylalkoxy,formyl or hydroxymethyl group already present in the ring.

Indole compounds having the following formula:

R g (IV) wherein R and R represents those substituents previouslymentioned for the heteroaromatic moiety can be prepared in two steps byreacting an indole compound having formula V:

with an aqueous solution of dimethylamine and an aqueous solution offormaldehyde to obtain a compound having formula (VI), wherein R and Rhave the meaning above defined, which compound is then reacted with analkali metal R -mercaptide (III) in the presence of dimethyl sulfate.The compounds of formula (V) can be readily prepared following theprocedures set forth in columns 2 and 3 of US. Pat. No. 2,825,734. Thenovel heterocyclic sulfoxide compounds wherein R and/or R are other thanhydrogen are prepared by one of two process steps, depending upon thetype of heterocyclic moiety involved. The following process may beillustrated by the following reaction schemes:

A. Where the heterocyclic moiety contains a nitrogen atom.

H a (Y) F inn-0mm (Y) n[Hot]CRuR halogen wherein R is an alkyl oralkenyl, R is hydrogen, alkyl or alkenyl and R and Y are previouslydefined.

Compound V1 is reacted with N-halosuccinimide in an inert solvent suchas carbon tetrachloride, preferably in the presence of a catalyticamount of peroxide, at or near ambient temperatures, to form compoundVII. Compound VII is then reacted in accordance with step I as shownpreviously for compound II, and the product VIII is further reacted inaccordance with step 2 as shown previously for compound IV.

B. Where the heterocyclic moiety contains oxygen and/or sulfur atoms.Using a sulfur derivative as an example, the following reaction schemeis followed:

Ii -5 (Y)nHCHz-SR4 (Y ,.-H-osm 6 S 1.5

R and R being hydrogen, alkyl or alkenyl; only one of R and R beinghydrogen at. the same time. The thiophene compound X is reacted with analkyl or alkenyl iodide in the presence of a strong base to obtaincompound Xl. If it is desired that R and R each be other than hydrogen,two equivalents of base and iodide are used. If one of R or R is to behydrogen, then one equivalent of base and iodide is used per equivalentof the thiophene compound.

Procedure A, may also be used to prepare thea substituents for all ofthe heterocyclic compounds. Therefore, it can be seen that bothprocedures A and B are applicable to the sulfur and oxygenheterocyclics.

Included within the scope of this invention are compounds wherein thesulfoxide moiety is attached to the nitrogen of the heterocyclicradical. These compounds are prepared by the following reaction scheme:

wherein R R R.,, Y and n are previously defined.

In this reaction scheme, the starting heterocyclic compound is reactedwith sodium hydride to activate the nitrogen. This activated compound issubsequently reacted with a chlorosulfide compound to form aheterocyclic sulfide compound, which compound is then oxidized to thedesired sulfoxide compound.

EXAMPLE 1 2-Ch1oromethy1-5-chlorothiophene A mixture of concentrated HCl(45.6 ml.) and 37 percent formalin (45 ml.) is saturated with dry HCl at-l0C. with stirring, and added in a slow stream to a mixture of-ch1orothiophene (71.6 grams) and zinc chloride at 35-40C. (1 gram). Thereaction mixture is then stirred for an additional 2 hours. Cold water(114 ml.) is then added. The oil which separates is washed two timeswith cold water. Dicyclohexylamine (2 cc.) is then added and the productdistilled under vacuum; the portion boiling at 90-96C/910 mm. iscollected.

EXAMPLE 2 2-Chloromethylthiazole Step A: Preparation of2-hydroxymethylthiazole Thiazole (17 grams, 14.2 mole) and 40 percentaqueous formalin solution (50 ml.) are heated at about 120C. for 8 hourswith agitation. The product is cooled and then acidified with 2.5N RC1and extracted with ether. The aqueous solution is neutralized with solidpotassium carbonate with stirring. The product is then extracted fourtimes with ether. The combined either extracts are dried over sodiumsulfate, filtered and concentrated. The yellow liquid remaining is takenup in 100 ml. of a mixture of 1:1 l-l Ozconc. HQ. The solution is thenfiltered and concentrated to give an oil which solidifies. The produceis triturated with ethanol, filtered and washed with ethanol to yield1.76 grams of 2-hydroxymethylthiazole hydrochloride, m.p. 123-12 5.5C.Step B: Preparation of 2-ch1oromethylthiazole The2-hydroxymethylthiazole hydrochloride (1.76 g.) from Step A is suspendedin 16 cc. of dried chloroform. Thionyl chloride (3.57 g., 0.03 mole) in10 cc. of chloroform is added over a time period of 5 minutes; themixture is stirred for 1 hour at room temperature and then refluxed on asteam bath for 1 hour and 45 minutes. Theproduct is cooled, concentratedunder vacuum, made alkaline with potassium carbonate and then extractedwith ether. The ether extract is dried over sodium sulfate, filtered,and the ether distilled off to give a residue of 2-chloromethylthiazole.

EXAMPLE 3 4-Chloromethylthiazole Step A: Preparation of4-hydroxymethylthiazole 4'-Formylthiazole (20 grams, 0.177 mole) andethanol (175 ml.) is added to sodium borohydride (3.4 g., 0.089 m.) in75 ml. of ethanol. The mixture is stirred and kept at about 25 2C. withan ice bath. The addition takes approximately 0.5 hour, and stirring iscontinued for an additional 1.0 hours at room temperature. Glacialacetic acid (6 ml.) in water (20 ml.) isadded dropwise. The produce isevaporated under vacuum to a small volume and extracted three times withchloroform. The chloroform solution is washed with saturated sodiumbicarbonate and then water. It is then dried and evaporated under vacuumto give 3.44 grams of 4-hydroxymethylthiazole. Step B: Preparation of4-Chloromethylthiazole Thionyl chloride (10 ml.) is added dropwise withcooling to the 4-hydroxymethylthiazole (3.44 grams) of Step A. Avigorous reaction results. After completion, the excess thionyl chlorideis then removed under vacuum to yield 4-chloromethylthiazolehydrochloride.

EXAMPLE 4 3-Chloromethylpyrazole Step A: Preparation of3-carboxypyrazole 3-Methylpyrazole (45 grams) is dissolved in 2,700 ml.of water. Powdered potassium permanganate (180 grams) is added inportions starting at room temperature and gradually heating to about C.on a steam bath. After the purple color is gone the product is filteredand the solid washed with water. The filtrate is evaporated under vacuumto a small volume and then acidified with concentrated l-lCl to pl-l-2and cooled. The precipitate is filtered and washed with cold water andair-dried to give 25.2 grams. The filtrate is evaporated to dryness,extracted with ethanol and evaporated to dryness again. The residue isextracted again with boiling ethanol and taken to dryness to give 23.6grams. The combined residues equal 48.8 grams. Step B:S-Ethoxycarbonylpyrazole Ethanol (300 ml.) is added to the3-carboxypyrazole (48.8 grams) of Step A. The mixture is saturated withHCl and then refluxed with stirring for about 5 hours. l-lCl isoccasionally passed in. The product is evaporated under vacuum and thesolid residue distributed between sodium carbonate solution andchloroform. The chloroform layer is dried and evaporated under vacuum.The residue is recrystallized from boiling methanol to give 36.2 gramsof 3-ethoxycarbonylpyrazole.

Step C: 3-I-lydroxymethylpyrazo1e Lithium aluminum hydride (16.3 g.) in1.5 liters of dry ether is refluxed with stirring overnight with 3-ethoxycarbonylpyrazole (30.3 grams). Water (about 55 milliliters) isadded dropwise and the ether is evaporated under vacuum. The residue istreated with methanol and saturated with carbon dioxide. The product isheated to boiling and filtered. The solid is washed with boilingmethanol and the methanol solution evaporated under vacuum to smallvolume. The product is then heated to boiling and filtered. Evaporationof the solvent yields 21.00 grams of a syrup which is the3-hydroxymethylpyrazole.

Step D: Preparation of 3-chloromethylpyrazole Thionyl chloride (35 ml.)is added dropwise to the 3- hydroxymethylpyrazole (21.0 g.) obtained in.Step C. The reaction mixture is then warmed on a steam bath forminutes. The excess thionyl chloride is removed under vacuum and theresidue washed with ether and dried under vacuum to yield 31.1 g. of3-chloromethylpyrazole hydrochloride.

EXAMPLE 5 4-Chloromethylimidazole Step A: Preparation of4,5-dicarboxyimidazole 4,5-Di(ethoxycarbonyl) imidazole (100 grams) in'400 ml. in 2.5N sodium hydroxide solution (400 ml.) is allowed to standat room temperature overnight. The disodium salt precipitates. It ismixed with concentrated HCl, cooled and filtered. The filtrate isstirred with fresh water, filtered and air-dried to give 72 grams of4,5-dicarboxyimidazole. Step B: Preparation of4-anilinocarbonylimidazole A mixture of 4,5-dicarboxyimidazole from StepA (200 grams) and aniline (1,000 ml.) is refluxed with stirring forthree days. The aniline is then removed by steam distillation. Theproduct is filtered, washed with water and then dissolved in acid. Theinsolubles are filtered ofi and the filtrate made alkaline with sodiumcarbonate. The precipitate is then filtered and washed with water. StepC: Preparation of 4carboxyimidazole The 4-anilinocarboxyimidazole fromStep B is added to 1,000 ml. of concentrated HCl and the mixturerefluxed for 4 hours and then taken to dryness. The residue is dissolvedin water, made alkaline with sodium carbonate, extracted with ether,charcoaled, adjusted to pH=4 with HCl, and allowed to stand in the coldovernight. The product is then filtered and washed with cold water. Thefiltrate is evaporated at room temperature and atmospheric pressure. Theresidue is washed with cold water and air-dried to yield 85 grams. StepD: Preparation of 4-ethoxycarbonylimidazole A mixture of the4-carboxyimidazole from Step C and 1% liters of ethanol is saturatedwith HC1 and refluxed until homogeneous. The reaction mixture isevaporated under vacuum. The residue is then dissolved in water,charcoaled, and treated with sodium bicarbonate. The solid is filtered,washed with cold water, and air-dried The aqueous filtrate is extractedwith chloroform, and the chloroform evaporated under vacuum. The totalyield of product is 73 grams. Step E: Preparation of4-hydroxymethylimidazole 4-Ethoxycarbonylimidazole (28 grams) from StepD is added portion-wise with stirring over a half hour period to lithiumaluminum hydride (10 g.) in 30 ml. of ether. After the addition iscomplete, the reaction mixture is allowed to stand overnight. Water (25ml.) is added dropwise. The resulting solid is filtered and suspended in300 ml. of hot methanol, saturated with carbon dioxide, and filtered.The product is extracted again with hot methanol. The extracts arecombined and evaporated under vacuum. The residue is taken up in 300 ml.of hot ethanol, filtered and evaporated under vacuum. The residue isthen treated with ethanolic HCl. The resulting solid is cooled, dilutedwith ether, and then filtered. The product is then washed with ether anddried under vacuum. Step F: Preparation of 4-chloromethylimidazole4-Hydroxymethylimidazole hydrochloride (10 grams) from Step E issuspended in 50 ml. of dry benzene, and 14 ml. of thionyl chloride in 50ml. of benzene is added slowly with stirring. After addition iscomplete, the reaction mixture is refluxed with stirring for 2 hours. Itis then evaporated under vacuum, to yield the 4-chloromethylimidazolehydrochloride.

EXAMPLE 6 2-lodomethyl-l ,4-benzodioxane A mixture of2-chloromethyl-l,4-benzodioxane (12 g.) in acetone (50 ml.) and sodiumiodide (9.75 g.) is stirred and refluxed for 3 days. The precipitatewhich forms is filtered off and washed with acetone. The filtrate isevaporated under vacuum and extracted with chloroform, to yield 14.81grams of an oil n 1.5780.

EXAMPLE 7 2-Methyl-3-methylthiomethyl-5-methoxyindole Step A:Preparation of 2-methyl-3- dimethylaminomethyl-S-methoxyindole2-Methyl-6-methoxyindole (8.0 grams) is dissolved in 35 ml. of glacialacetic acid with warming. To this solution is added 25 percent aqueousdimethylamine (9.0 g.) and 37 percent formation solution (4.1 g.). Aprecipitate forms and the mixture is stirred at room temperatureovernight. It is then diluted with water and methanol and evaporatedunder vacuum. The residue is extracted with water and made alkaline withammonium hydroxide. The precipitate which forms is filtered off, washedwith water, and air-dried to give 2-methyl-3-dimethylaminomethyl-6-methoxyindole, m.p. 142-147C. The product isdissolved in dilute l-lCl, extracted two times with ether, filtered, andmade alkaline with 2.5N sodium hydroxide. It is then cooled, filtered,washed with water, and air-dried. The product is purified byrecrystallization from aqueous acetone solution to yield a product, m.p.245249C. Analysis Calcd. for G i-1 F1 0: C, 71.52; H, 8.31

Found: C, 71.36; H, 8.32. Step B: Preparation of2-methyl-3-methy1thiomethyl-5- methoxyindole To2-methyl-3-dimethylaminomethyl-6-methoxyindole (2.183 g., 0.01 m.) in 75ml. of ethanol is added sodium methyl mercaptide (0.012 m.). The mixtureis stirred while dimethyl sulfate (1.9 ml.,'2.52 g.) is slowly added.The reaction mixture is stirred at room temperature for 4 hours, heatedto reflux for 4 hours, and then let stand at room temperature overnight.The product is evaporated under vacuum and distributed between water andchloroform. The chloroform solution is washed one time with dilute HCland three times with water; it is then dried and evaporated under vacuumto give the product.

EXAMPLE 8 1-Methylthiomethylimidazole To a suspension of 0.1 moles ofsodium hydride in 50 cc. of dry dimethylformimide, which is stirredunder nitrogen and maintained at -5C., is added a solution of 0.1 molesof imidazole in 50 cc. of dry dimethylformamide. The reaction mixture isstirred for 30 minutes after the evolution of hydrogen ceases. Thenthere is added a solution of 0.12 moles of chloromethylmethylsulfide in50 cc. of dry dimethylformamide and the reaction mixture is stirredovernight at room temperature. The reaction mixture is concentrated invacuo, extracted well with boiling chloroform and the combinedchloroform extracts are chromatographed on silica gel. Elution withmethanol (05) in methylene chloride gives l-methylthiomethylimidazole.

The 2-substituted imidazoles-may be prepared by reacting the followingZ-irnidazoles with chloromethylmethyl sulfide in the presence of sodiumhydride according to the above procedure.

Starting Material Productsl-methylthiomethyll-methylthiomethyll-methylthiomethyl- Z-butylimidazolel-mcthylthiomethyl- 2-bromoimidazole l -methylthiomethyl-2-nitroimidazole l-methylthiomethyl- Z-methylthioimidazoleZ-methylimidazole 2'ethylimidazole Z-butylim idazole Z-bromoimidazole2-nitroimidazolc 2-methylthioimidazole 2-m ethylimidazoleZ-ethylimidazole Starting Material Products 4-methylimidazoleS-methylimidazole l-methylthiomethyl-4 -methylirnidazoleI-meIhyIthiOmethyl-S -methylimidazole 4-ethylimidazolel-rnethylthiomethyl-4 ethylimidazole S-ethylimidazolel-methylthiorhethyl-S -ethylimidazole 4-propylimidazolel-methylthiomethyl-4 -propylirnidazole S-propylimidazolel-methylthiomethyl-S -propylimidaz0le 4-t-butylimidazolel-methylthiomethyl-4 -t-butylimidazole S-t-butylimidazolel-methylthiomethyl-S -t-butylimidazole -nitroimidazole -nitroimidazole-bromoimidazole -bromoimidazole -methoxyimidazole -methoxyimidazolel-methylthiornethyl-4 l-methylthiomethyl-S l-methylthiomethyl-4l-methylthiomethyl-S lmethylthiomethyl-4 l-m ethylthiomethyl-S4-nitroimidazole S-nitroimidazole 4-bromoimidazole S-bromoimidazole4-methoxyimidazole S-methoxyimidazole Similarly, when benzimidazole isused in place of the above imidazole, there is obtainedmethylthiomethylbenzimidazole.

When the 3(or 5)-substituted pyrazoles are used in place of theimidazoles and reacted according to the above procedure, the followingcorresponding 3-substituted andS-substituted-l-methylthiomethylpyrazoles are obtained:

Starting Material Products l-methylthiomethyl-3(or 5)- methylpyrazolel-methylthiomethyl-3(or 5)- ethylpyrazole l-methylthiomethyl-3(or 5propylpyrazole l-methylthiomethyl-3(or 5 butylpyrazolel-methylthiomethyl--(or 5)- bromopyraz ole 3(or 5 )-methylpyrazole 3(or5 )-ethylpyrazple 3(or S )-propylpyrazole 3(or 5 )-butylpyrazole 3(or5)-bromopyrazole 1 When the 4-substitutedpyrazoles are used in place ofthe imidazoles and reacted according to the above procedure, thefollowing corresponding 4-substitutedl-methylthiomethylpyrazoles areobtained:

Starting Material Products 4-methylpyrazole l-methylthiomethyl-4-methylpyrazole 4-ethylpyrazole l-methylthiomethyl-4 -ethylpyrazole4-propylpyrazole l-methylthiomethyl-4 -propylpyrazole 4-bromopyrazolel-methylthiomethyl-4 -bromopyrazole 4-chloropyrazole lmethylthiomethyl-4-chloropyrazolc 4-nitropyrazole l-methylthiomethyl-4 -nitropyrazole4-ethoxypyrazole l-methylthiomethyl-4 -ethoxypyrazole EXAMPLE 9 EXAMPLEl0 4-Hydroxy-2-methylthiomethylthiazole A mixture of 0.1 moles ofmethylthiothioacetamide and 0.15 moles of chloroacetic acid are refluxedfor 3 hours in 250 cc. of toluene under nitrogen The reaction mixture isfiltered while hot and then concentrated to yield crude4-hydroxy-2-methylthiomethylthiazole.

EXAMPLE 1 l 4-Methoxy-2-methylthiomethylthiazole To a stirred suspensionof 0.05 moles of sodium hydride in 50 cc. of dry dimethylformamide at0-5 is added dropwise 0.05 moles of 4-hydroxy-2-methylthiomethylthiazole in 50 cc. dry dimethylformamide. After theevolution of hydrogen has ceased, there is added dropwise 0.05 moles ofmethyl iodide. The reaction mixture is stirred at room temperatureovernight, concentrated and extracted between ether and water. Theaqueous layer is separated, extracted well with ether and the combinedether extracts dried over sodium sulfate and concentrated to yield crude4- methoxy-2-methylthiomethylthiazole. Chromatography on 500 gm. ofsilica gel and elution with methanol in methylene chloride (o-5 percent)gives pure 4-methoxy-Z-methylthiomethylthiazole.

EXAMPLE l2 5-Chloro-2-methylsulfinylmethylthiophene A.5-Chloro-2-methylthiomethylthiophene A solution of 0.1 moles of sodiumhydroxide in 200 cc. of ethanol is saturated with methyl mercaptan.There is then added with stirring a solution of 0.1 moles of2-chloromethyl-5-chlorothiophene in 50 cc. of ethanol. The reactionmixture is refluxed overnight, cooled and 500 cc. of ether added. Themixture is filtered and concentrated to give crude 2-methylthiomethyl-S-chlorothiophene. B.5-Chloro-Z-methylsulfinylmethylthiophene To 210 ml. of a 0.5M solutionof sodium metaperiodate at is added a 0.1 moles of -chloro-2-methylthiomethylthiophene. The reaction mixture is stirred overnight at0-5C. The precipitated NalO is removed by filtration and the filtrateextracted well with chloroform. The combined chloroform extracts aredried over sodium sulfate and concentrated in vacuo. The residue ischromatographed on 500 grams of silica gel. Elution withmethanol-methylene chloride (0-10 percent) gives5-chloro-2-methylsulfinylmethylthiophene.

Similarly, when 4-chlor0methylpyridine, 2- chloromethylpyridine,3-chloromethylpyridine, 2- chloromethylthiazole, 4-chloromethylthiazole,3- chloromethylpyrazole, 4-chloromethylimidazole, 2-

chloromethylbenzimidazole or 2-iodomethyl-l,4- benzodioxane obtained inaccordance with the procedure of Examples 1-7 are used in place of 2-chloromethyl-S-chlorothiophene in the above example, there is obtainedthe corresponding heterocyclic sulfinyl compound. For example when3-chloromethylpyrazole is reacted with methylmercaptan and the resultant3-methylthiomethylpyrazole is oxidized with sodium periodate, there isobtained 3-methylsulfinylmethylpyrazole.

Similarly, when the l-methylthiomethyl pyrazole compounds obtained inaccordance with the procedure of Example 8 are used in place of5-chloro-2- methylthiomethylthiophene in part B of the above example,there are obtained the corresponding l-methylsulfinylmethyl pyrazolecompounds. For example when 4-methyl-l-methylthiomethylpyrazole isoxidized with sodium periodate, there is obtained 4-methyl- 1-methylsulfinylmethylpyrazole.

Similarly, when the 2-methylthiomethylthiazole, the4-substituted-2-methylthiomethylthiazoles obtained in accordance withthe procedure of Example 9, 4- hydroxy-Z-methylthiomethylthiazoleobtained in accordance with the procedure of Example 10, and 4-methoxy-Z-methylthiomethylthiazole obtained in acd e t the rocedur of Ex1 l are sed in giiic g S c h oro- -methylt iometh y 'i hiop enein part Bof the above example, there are obtained the correspondingZ-methylsulfinylmethylthiazole compounds.

Similarly, when 2-methyl-3-methylthiomethyl-5- methoxyindole obtained inaccordance with the procedure of Example 7 is used in place of5-chloro-2- methylthiomethylthiophene in part B of the above example,there is obtained 2-methyl-3-methylsulfinylmethyl-S-methoxyindole.

What is claimed is:

1. A compound of the formula:

YJH N/ CHrSDR wherein Y is hydrogen, halogen, lower alkyl, lower alkoxy,or nitro and R is lower alkyl.

2. 3-Methylsulfinylmethylpyrazole.

3. 4-Methyll -methylsulfinylmethylpyrazole.

2. 3-Methylsulfinylmethylpyrazole. 3.4-Methyl-1-methylsulfinylmethylpyrazole.